Aspartoacylase-LacZ Knockin Mice: An Engineered Model of Canavan DiseaseReport as inadecuate

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Canavan Disease CD is a recessive leukodystrophy caused by loss of function mutations in the gene encoding aspartoacylase ASPA, an oligodendrocyte-enriched enzyme that hydrolyses N-acetylaspartate NAA to acetate and aspartate. The neurological phenotypes of different rodent models of CD vary considerably. Here we report on a novel targeted aspa mouse mutant expressing the bacterial β-Galactosidase lacZ gene under the control of the aspa regulatory elements. X-Gal staining in known ASPA expression domains confirms the integrity of the modified locus in heterozygous aspa lacZ-knockin aspalacZ-+ mice. In addition, abundant ASPA expression was detected in Schwann cells. Homozygous aspalacZ-lacZ mutants are ASPA-deficient, show CD-like histopathology and moderate neurological impairment with behavioural deficits that are more pronounced in aspalacZ-lacZ males than females. Non-invasive ultrahigh field proton magnetic resonance spectroscopy revealed increased levels of NAA, myo-inositol and taurine in the aspalacZ-lacZ brain. Spongy degeneration was prominent in hippocampus, thalamus, brain stem, and cerebellum, whereas white matter of optic nerve and corpus callosum was spared. Intracellular vacuolisation in astrocytes coincides with axonal swellings in cerebellum and brain stem of aspalacZ-lacZ mutants indicating that astroglia may act as an osmolyte buffer in the aspa-deficient CNS. In summary, the aspalacZ mouse is an accurate model of CD and an important tool to identify novel aspects of its complex pathology.

Author: Nadine Mersmann, Dmitri Tkachev, Ruth Jelinek, Philipp Thomas Röth, Wiebke Möbius, Torben Ruhwedel, Sabine Rühle, Wolfgang Web



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